Lead optimization of 4-acetylamino-2-(3,5-dimethylpyrazol-1-yl)-6-pyridylpyrimidines as A2A adenosine receptor antagonists for the treatment of Parkinson's disease.
4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-pyrimidines bearing substituted pyridyl groups as C-6 substituents were prepared as selective adenosine hA2A receptor antagonists for the treatment of Parkinson's disease. The 5-methoxy-3-pyridyl derivative 6g (hA2A Ki 2.3 nM, hA1 Ki 190 nM) was orally active at 3 mg/kg in a rat HIC model but exposure was poor in nonrodent species, presumably due to poor aqueous solubility. Follow-on compound 16a (hA2A Ki 0.83 nM, hA1 Ki 130 nM), bearing a 6-(morpholin-4-yl)-2-pyridyl substituent at C-6, had improved solubility and was orally efficacious (3 mg/kg, HIC) but showed time-dependent cytochrome P450 3A4 inhibition, possibly related to morpholine ring metabolism. Compound 16j (hA2A Ki 0.44 nM, hA1 Ki 80 nM), bearing a 6-(4-methoxypiperidin-1-yl)-2-pyridyl substituent at C-6, was sparingly soluble but had good oral exposure in rodent and nonrodent species, had no cytochrome P450 or human ether-a-go-go related gene channel issues, and was orally efficacious at 1 mg/kg in HIC and at 3 mg/kg for potentiation of l-dopa-induced contralateral rotations in 6-hydroxydopamine-lesioned rats.
Zhang
Xiaohu
X
Department of Medicinal Chemistry, Neurocrine Biosciences, 12780 El Camino Real, San Diego, California 92130, USA.
Tellew
John E
JE
Luo
Zhiyong
Z
Moorjani
Manisha
M
Lin
Emily
E
Lanier
Marion C
MC
Chen
Yongsheng
Y
Williams
John P
JP
Saunders
John
J
Lechner
Sandra M
SM
Markison
Stacy
S
Joswig
Tanya
T
Petroski
Robert
R
Piercey
Jaime
J
Kargo
William
W
Malany
Siobhan
S
Santos
Mark
M
Gross
Raymond S
RS
Wen
Jenny
J
Jalali
Kayvon
K
O'Brien
Zhihong
Z
Stotz
Carol E
CE
Crespo
María I
MI
Díaz
José-Luis
JL
Slee
Debora H
DH
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006220:Haloperidol; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D010300:Parkinson Disease / Q000188:drug therapy*; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D058917:Adenosine A2 Receptor Antagonists; D008024:Ligands; D011720:Pyrazoles; D011743:Pyrimidines; D006220:Haloperidol